Do current therapeutic anti-Aβ antibodies for Alzheimer’s disease engage the target?

Abstract

Reducing amyloid-β peptide (Aβ) burden at the pre-symptomatic stages of Alzheimer's disease (AD) is currently the advocated clinical strategy for treating this disease. The most developed method for targeting Aβ is the use of monoclonal antibodies including bapineuzumab, solanezumab and crenezumab. We have synthesized these antibodies and used surface plasmon resonance (SPR) and mass spectrometry to characterize and compare the ability of these antibodies to target Aβ in transgenic mouse tissue as well as human AD tissue. SPR analysis showed that the antibodies were able to bind Aβ with high affinity. All of the antibodies were able to bind Aβ in mouse tissue. However, significant differences were observed in human brain tissue. While bapineuzumab was able to capture a variety of N-terminally truncated Aβ species, the Aβ detected using solanezumab was barely above detection limits while crenezumab did not detect any Aβ. None of the antibodies were able to detect any Aβ species in human blood. Immunoprecipitation experiments using plasma from AD subjects showed that both solanezumab and crenezumab have extensive cross-reactivity with non-Aβ related proteins. Bapineuzumab demonstrated target engagement with brain Aβ, consistent with published clinical data. Solanezumab and crenezumab did not, most likely as a result of a lack of specificity due to cross-reactivity with other proteins containing epitope overlap. This lack of target engagement raises questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventative clinical trials for AD.

Amyloid-β Peptide Aβ3pE-42 Induces Lipid Peroxidation, Membrane Permeabilization, and Calcium Influx in Neurons

“…QC knock-out does not completely inhibit pE-A␤ formation in transgenic AD mouse models, however (68), suggesting that multiple pathways of pE-A␤ formation may exist. Antibodies currently under development as passive vaccine therapies for AD show significant differences in their capacity to bind amino-truncated A␤ species (69) and thus may fail to remove pE-A␤ and its precursors (A␤3-40/42 and A␤11-40/42). Individuals with AD may therefore require different therapeutic interventions to target distinct A␤ isoforms and their specific mechanisms of toxicity.…”

Alzheimer’s Disease: Lessons Learned from Amyloidocentric Clinical Trials

“…Although the target engagement is unclear, the candidate has passed the safety evaluation of a phase I trial with no evidence of inducing ARIA-E or ARIA-M and has been tested in two phase II trials (ABBY and BLAZE trials). The ABBY trial involved 431 patients with mild-to-moderate AD given 15 mg/kg/month of the compound, while the BLAZE trial was a second smaller phase II study that involved 91 patients with mild-to-moderate AD [120]. The compound is also being tested in pre-symptomatic carriers of autosomal dominant pre-senilin mutations in comparison with placebo for a study duration of 5 years.…”

The amyloid hypothesis is too good to be true

“…She also said 58% of these individuals had APOE4, compared to only 24% of the individuals without elevated brain amyloid. When Watt et al [112] used SELDI-TOF-MS (surface-enhanced laser desorption-ionization time-of-flight mass-spectroscopy) to study the targeting specificity and affinity of the anti-Aβ antibodies being used in the preventive Alzheimer trials, here is what they found: bapineuzumab bound to Aβ peptides isolated from the brain amyloid, while solanezumab and crenezumab did not. Both solanezumab and crenezumab bound to some 200 other proteins unrelated to Aβ peptide.…”

“…Both solanezumab and crenezumab bound to some 200 other proteins unrelated to Aβ peptide. It is no wonder if Watt et al [112] raised "questions as to whether solanezumab and crenezumab are suitable drug candidates for the preventive clinical trials for Alzheimer's disease." When Siemers et al [113] at Lilly argued against these findings, Watt et al [114] defended their findings.…”